The present invention relates to a new use, in particular a new use for a compound group comprising derivatives of rapamycin, in free form or in pharmaceutically acceptable salt or complex form. Suitable derivatives of rapamycin include e.g. compounds of formula I 
wherein
X is (H,H) or O;
Y is (H,OH) or O;
R1 and R2 are independently selected from
H,. alkyl, arylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxycarbonylalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, acyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, acylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, dialkyl-dioxolanylalkyl, di(alkoxycarbonyl)-triazolyl-alkyl and hydroxy-alkoxy-alkyl; wherein xe2x80x9calk-xe2x80x9d or xe2x80x9calkylxe2x80x9d is C1-6alkyl, branched or linear; xe2x80x9carylxe2x80x9d is phenyl or tolyl; and acyl is a radical derived from a carboxylic acid; and
R4 is methyl or
R4 and R1 together form C2-6alkyl;
provided that R1 and R2 are not both H; and hydroxyalkoxyalkyl is other than hydroxyalkoxymethyl.
Such compounds are disclosed in WO 94/09010 the contents of which, in particular with respect to the compounds, are incorporated herein by reference.
Acyl as may be present in R1 or R2, is preferably RaCOxe2x80x94 wherein Ra is C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, aryl, aryl C1-6alkyl (wherein aryl is as defined above) or heteroaryl, e.g. a residue derived from a 5 or 6 membered heterocycle comprising N, S or O as a heteroatom and optionally one or two N as further heteroatoms. Suitable heteroaryl include e.g. pyridyl, morpholino, piperazinyl and imidazolyl.
Examples of such compounds include:
1. 40-O-Benzyl-rapamycin
2. 40-O-(4xe2x80x2-Hydroxymethyl)benzyl-rapamycin
3. 40-O-[4xe2x80x2-(1,2-Dihydroxyethyl)]benzyl-rapamycin
4. 40-O-Allyl-rapamycin
5. 40-O-[3xe2x80x2-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2xe2x80x2-en-1xe2x80x2-yl]-rapamycin
6. (2xe2x80x2E,4xe2x80x2S)-40-O-(4xe2x80x2,5xe2x80x2-Dihydroxypent-2xe2x80x2-en-1xe2x80x2-yl)-rapamycin
7. 40-O-(2-Hydroxy)ethoxycarbonylmethyl-rapamycin
8. 40-O-(2-Hydroxy)ethyl-rapamycin
9. 40-O-(3-Hydroxy)propyl-rapamycin
10. 40-O-(6-Hydroxy)hexyl-rapamycin
11. 40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin
12. 40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin
13. 40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin
14. 40-O-(2-Acetoxy)ethyl-rapamycin
15. 40-O-(2-Nicotinoyloxy)ethyl-rapamycin
16. 40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin
17. 40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin
18. 40-O-[2-(N-Methyl-Nxe2x80x2-piperazinyl)acetoxy]ethyl-rapamycin
19. 39-O-Desmethyl-39,40-O,O-ethylene-rapamycin
20. (26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin
21. 28-O-Methyl-rapamycin
22. 40-O-(2-Aminoethyl)-rapamycin
23. 40-O-(2-Acetaminoethyl)-rapamycin
24. 40-O-(2-Nicotinamidoethyl)-rapamycin
25. 40-O-(2-(N-Methyl-imidazo-2xe2x80x2-ylcarboxamido)ethyl)-rapamycin
26. 40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin
27. 40-O-(2-Tolylsulfonamidoethyl)-rapamycin
28. 40-O-[2-(4xe2x80x2,5xe2x80x2-Dicarboethoxy-1xe2x80x2,2xe2x80x2,3xe2x80x2-triazol-1xe2x80x2-yl)-ethyl]-rapamycin
A preferred compound is e.g. 40-O-(2-hydroxy)ethyl-rapamycin (referred thereafter as Compound A).
Compounds of formula I have, on the basis of observed activity, e.g. binding to macrophilin-12 (also known as FK-506 binding protein or FKBP-12), e.g. as described in WO 94/09010, been found to be useful e.g. as immunosuppressants, e.g. in the treatment of acute allograft rejection.
Organ transplants of liver, kidney, lung and heart are now regularly performed as treatment for endstage organ disease. Because of the current shortage of human donors for transplantable allografts, attention has focused on the possibility of using xenografts (transplants between species) in transplantation. One of the major obstacles in transplanting successfully xenografts in humans is immunological.
A further obstacle in allo- and xenotransplantation is the chronic rejection and thus organ transplantation is not yet a clinically viable solution to irreversible organ disease.
Chronic rejection, which manifests as progressive and irreversible graft dysfunction, is the leading cause of organ transplant loss, in some cases already after the first postoperative year. The clinical problem of chronic rejection is clear from transplantation survival times; about half of kidney allografts are lost within 5 years after transplantation, and a similar value is observed in patients with heart allografts.
Chronic rejection is considered as a multifactorial process in which not only the immune reaction towards the graft but also the response of the blood vessel walls in the grafted organ to injury (xe2x80x9cresponse-to-injuryxe2x80x9d reaction) plays a role. The variant of chronic rejection with the worst prognosis is an arteriosclerosis-like alteration, also called transplant vasculopathy, graft vessel disease, graft arteriosclerosis, transplant coronary disease, etc. This vascular lesion is characterized by migration and proliferation of smooth muscle cells, probably under influence of growth factors that are amongst others synthesized by endothelial cells. This leads to intimal proliferation and thickening, smooth muscle cell hypertrophy repair, and finally to gradual luminal obliteration (vascular remodelling). It appears to progress also through repetitive endothelial injury induced amongst others by host antibody or antigen-antibody complexes; also so-called non-immunological factors like hypertension, hyperlipidemia, hypercholesterolemia etc. play a role.
Chronic rejection appears to be inexorable and uncontrollable because there is no known effective treatment or prevention modality. Thus, there continues to exist a need for a treatment effective in preventing, controlling or reversing manifestations of chronic graft vessel diseases.
There also continues to exist a need to prevent or treat restenosis or vascular occlusions as a consequence of proliferation and migration of intimal smooth muscle cell, e.g. induced by vascular surgeries such as angioplasty.